The road from discovering a potential drug to getting the therapy into the hands of patients is a long and uncertain one.
Konstantin Petrukhin, Ph.D., ought to know.
In 2011, after years working at the bench, the professor of ophthalmic sciences at Columbia University Medical Center, discovered a promising drug candidate for treating the most common form of age-related macular degeneration (AMD). This blinding eye disease affects millions of Americans, and atrophic or “dry” AMD accounts for 90% of cases. There is currently no treatment for dry AMD.
The therapy, known as LBS-008 (formerly BPN-14967), appears to be promising for other retinal degenerative diseases such as Stargardt disease, a rare, inherited condition that causes vision loss during childhood and young adulthood.
The cherry on top: Petrukhin identified a biomarker that could easily be measured in a person’s blood to confirm the drug’s level of activity and fine tune dosage. LBS-008 is a tablet taken by mouth, sparing patients the need for an injection into the eye, which is a common mode of delivery for therapies that must reach the light-sensitive retinal tissue at the back of the eye.
Despite all that LBS-008 had in its favor, Petrukhin had only cleared the first hurdle. The next would involve finding a biopharmaceutical firm willing to take the risk of shepherding the new drug to the market.
For every drug that successfully makes it into the hands of patients, nine fail somewhere along the clinical trial pipeline. On average, it can take up to 15 years and $1 billion to bring a new drug to market, accounting for the failed drug candidates.
Much of that time and money is spent meeting rigorous regulatory requirements established by the U.S. Food and Drug Administration. These requirements are in place to safeguard the health of patients. Before a new drug is FDA-approved, it must demonstrate safety and efficacy in a lengthy three-phase clinical trial process.
And before clinical trials can even begin testing in humans, the FDA requires preliminary support for the safety, efficacy, and quality of the investigational therapy. That means information about the agent’s performance in preclinical animal studies assessing efficacy and toxicology, detailed clinical protocols and manufacturing plans.
“It takes a team of experts with a wide range of expertise to advance a candidate drug to clinical trials,” Petrukhin said. Basic science researchers in academia typically do not have access to all the necessary skills to get their novel therapeutics strategies to the point where a biopharmaceutical firm would be interested in taking on a promising drug through the clinical trials process.
For that expertise, Petrukhin turned to the National Institutes of Health Blueprint Neurotherapeutics Network for Small Molecules. Launched in 2011, the network provides a framework for researchers like Petrukhin, who have a promising candidate treatment for an unmet medical need, to attract pharmaceutical company interest.
How the NIH Blueprint program works
The network, which is funded and administered by a consortium of NIH institutes, including the National Eye Institute, provides principal investigators like Petrukhin access to a full range of industry-style drug development services and expertise. Each project forms a lead development team composed of the principal investigator, as well as NIH staff and industry consultants hired by NIH. The network provides principal investigators with access to Contract Research Organizations (CROs) and a team providing cross-functional expertise – from assay development and pharmacology to medicinal chemistry, pharmacokinetics, toxicology, formulation development, and Phase I clinical testing.
“If a researcher’s project requires a consultant that has a specific type of expertise such as regulatory affairs or drug manufacturing, we have a diverse group of consultants with years of experience in the pharmaceutical industry who provide guidance in areas such as the FDA regulatory process and the steps involved in developing a useful drug product, free of charge. Essentially, researchers have access to a virtual pharma company tailored to their project through their lead development team and NIH contracts,” said Mary Ann Pelleymounter, Ph.D., a scientific project manager for the Blueprint Neurotherapeutics Network for Small Molecules.
“Academic and small business researchers are provided with the tools and resources to navigate the drug discovery process in an efficient way that is intended to optimize the probability of success,” added Pelleymounter who managed Petrukhin’s lead development team.
The Blueprint Neurotherapeutics Network was NIH’s response to the fact that most nervous system and neurodegenerative disorders lack effective treatment, and most of the potential neurotherapeutic agents identified from basic research do not make it to human testing.
“As tough as it is to bring new drugs to market in general, neurotherapeutics have an even steeper hill to climb. They have a long track record of failure and a limited pool of validated treatment targets and strategies on which to build, which resulted in pharma companies exiting the neuroscience research area,” said Charles Cywin, Ph.D., program director for the Blueprint Neurotherapeutics Network.
Inherited neurological disorders also tend to affect relatively small populations, which reduces the potential upside for a company taking on the risk.
Finally, neurotherapeutic clinical trials often are expensive because many of the disorders, such as AMD, are neurodegenerative, progressing over years, necessitating lengthy and costly trials to determine if a treatment is working.
“The Blueprint Network aims to de-risk candidate therapeutic agents to the point that these projects are attractive investments for pharma, biotech and venture firms, and allows these exciting basic research findings to become potential new drugs to reach patients efficiently,” Pelleymounter said.
In 2011, Petrukhin’s project was selected by the NIH Blueprint Program and received sufficient funding and contract resources to support development of LBS-008 from early discovery through Phase Ia clinical testing.
In 2017, the San Diego-based biopharmaceutical company Belite Bio Inc. (formerly Lin Bioscience) selected LBS-008 for its portfolio to support clinical testing of this candidate therapeutic. By June 2021, the company had launched a late-stage Phase 3 clinical trial of LBS-008 in patients with Stargardt disease. As a potential treatment for a rare disease, testing the drug first in Stargardt enabled LBS-008 to be granted an orphan-drug designation, which qualifies Belite Bio for tax credits and an extended period of market exclusivity after approval. If LBS-008 is approved, it will accelerate the clinical trial process for an atrophic AMD indication.
Under the agreement, Belite Bio holds exclusive global licensing rights. Along with other co-inventors, Petrukhin maintains relevant patents. Columbia University holds the rights to the intellectual property portfolio. If approved, the drug will be marketed as Tinlarebant.
How the LBS-008 therapy works
Petrukhin designed his therapeutic strategy based on a long-observed phenomenon in patients with atrophic AMD and Stargardt disease. Their retinas tend to have an accumulation of lipofuscin, a yellow-brown lipid-based substance associated with aging. Granules of lipofuscin accumulate in a retinal layer called the retinal pigment epithelium (RPE), which supports the health of light-sensing photoreceptors. In both atrophic AMD and Stargardt disease, vision loss occurs when photoreceptors die, but their death happens secondary to the loss of RPE cells. Petrukhin and others hypothesized that reducing harm from lipofuscin might prolong RPE and photoreceptor survival.
The best studied toxic component of lipofuscin is the bisretinoid A2E, a by-product of the normal visual cycle, the vital biochemical pathway that regenerates visual pigment, and is important for converting light (photons) into electrical signals sent from the retina to the brain.
A2E production depends on the influx of retinol from blood to the RPE. What’s more, retinol uptake from blood circulation is dependent on the function of retinol-binding protein 4 (RBP4).
Petrukhin asked whether reducing the retinoid load of the visual cycle with an RBP4 antagonist might reduce A2E production just enough to stave off AMD and Stargardt disease, without interfering too much with the necessary biochemical pathway required for vision.
In his search for a way to inhibit RBP4, Petrukhin came across some papers describing an RBP4 antagonist compound that had initially been developed by the pharmaceutical company Amgen as a potential treatment for diabetes. Long since shelved for diabetes, Petrukhin began tests to see if the RBP4 antagonist might lead to a therapeutic reduction of lipofuscin bisretinoids. That compound (called A1120) was a starting point for optimization that eventually yielded LBS-008, a drug candidate that is currently in clinical development.
In unpublished mouse studies, LBS-008 reduced levels of RBP4 in the blood by 93% after 12 weeks, and A2E levels were reduced by 80% in treated mice compared to controls.
Furthermore, in mouse models of Stargardt disease, compared with controls, LBS-008-treated animals had significantly greater preservation in the thickness of their outer nuclear layer, a cell layer that consists of photoreceptors that becomes thinner with disease-related damage.
Petrukhin notes that several other companies have since adopted similar RBP4 antagonist strategies for reducing lipofuscin bisretinoids. “So, the field has become very crowded, which tells we made the right choice,” he said.
Today, Petrukhin’s lab is continuing to explore optimal strategies for developing the next generation of RBP4 antagonists, which are not only potential therapies for eye diseases, but may also be used as a treatment for metabolic diseases such as non-alcoholic fatty liver disease and type 2 diabetes.
Building on the success of the initial Blueprint Neurotherapeutics Network for Small Molecules (that is, therapies like Petrukhin’s that enter cells and work at a molecular level), the program recently expanded to support lead optimization for biologic therapies, which are treatments derived from substances made from living organisms.
“This is an exciting new opportunity for vision scientists working on some of the most promising biologic-based therapies, such as gene therapies, or cell-replacement therapies,” said Thomas Greenwell, Ph.D., a program director for the NEI and for Blueprint. To learn more about the Blueprint Neurotherapeutics Network: Biologic-based Drug Discovery and Development for Disorders of the Nervous System, visit https://neuroscienceblueprint.nih.gov/neurotherapeutics/bpn-biologics
Clinical trials testing LBS-008, also known as BPN-14967 are NCT05244304, NCT04005807, NCT05266014, NCT03735810.
Blueprint Neurotherapeutics Network (BPN) for Small Molecules
Age-related macular degeneration
Safety and Tolerability Study of LBS-008 in Healthy Adult Subjects After Single and Multiple Doses on Clinical Trials.gov
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2. Wouters, O.J., M. McKee, and J. Luyten, Estimated Research and Development Investment Needed to Bring a New Medicine to Market, 2009-2018. JAMA, 2020. 323(9): p. 844-853.